5‐ HT modulates the rat mesenteric vasopressor outflow by 5‐HT 1D sympatholytic receptors

Hernández-Abreu

Morán

et al. 2020

Preprint

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Abstract Background: In normoglycaemic pithed rats, cardiac sympathetic control is modulated by serotonin (5-hydroxytryptamine; 5‑HT), which inhibits the cardioaccelerator sympathetic outflow via the activation of 5-HT 1B , 5-HT 1D and 5-HT 5A receptors. Notwithstanding, type 1 diabetes impairs the functionality of the cardiac sympathetic innervation and leads to cardiovascular complications including cardiac autonomic neuropathy. On this basis, the present study investigated whether the influence of 5-HT on cardiac noradrenergic neurotransmission is altered in type 1 diabetic rats, by analysing the profile of the 5-HT receptors involved and their peripheral expression. Methods: Type 1 diabetes was induced in male Wistar rats with a single injection of streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by either electrical preganglionic stimulation (C 7 ‑T 1 ) of the cardioaccelerator sympathetic outflow or i.v. bolus injections of exogenous noradrenaline. Immunohistochemistry analyses were performed to study the expression of 5‑HT 1B , 5-HT 1D and 5-HT 5A receptors in the stellate (sympathetic) ganglion obtained from normoglycaemic and diabetic rats. Results: The increases in heart rate evoked by both cardiac sympathetic stimulation and exogenous noradrenaline were not modified after saline in diabetic rats. Moreover, i.v. continuous infusions of 5‑HT induced a cardiac sympatho-inhibition that was mimicked by the 5‑HT 1/5A receptor agonist 5‑carboxamidotryptamine, but not by the agonists indorenate (5-HT 1A ), CP 93,129 (5‑HT 1B ), PNU 142633 (5-HT 1D ), or LY344864 (5‑HT 1F ) in the diabetic group. In contrast, the above agonists at 5-HT 1B , 5-HT 1D and 5-HT 1/5A receptors mimicked 5-HT-induced sympatho-inhibition in normoglycaemic rats. In diabetic animals, i.v. administration of SB 699551 (1 mg/kg; 5‑HT 5A receptor antagonist) abolished 5‑CT-induced cardiac sympatho-inhibition. Finally, the immunohistochemistry analysis in the stellate ganglion showed that, as compared to normoglycaemic rats, in diabetic rats (P<0.05): (i) the expression of 5-HT 1B receptors was slightly higher, whereas that of 5-HT 1D receptors was slightly lower; and (ii) there was a clear overexpression of 5-HT 5A receptors. Conclusions: Taken together, these results show the prominent role of the peripheral overexpression of prejunctional 5-HT 5A receptors in the inhibition of the cardiac sympathetic drive in type 1 diabetic rats. These findings may represent a new pharmacological strategy for the treatment of diabetes-related cardiac abnormalities.

Section: Systemic Haemodynamic Variablesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exclusive Peripheral Overexpression of 5-HT5A Receptors is Involved in 5‑HT‑Induced Cardiac Sympatho-Inhibition in Type 1 Diabetic Rats

Hernández-Abreu

Morán

et al. 2020

Preprint

Self Cite

Section: Introductionmentioning

confidence: 99%

“…The serotonergic system plays a pivotal function in cardiovascular homeostasis, both by directly regulating blood vessel contraction and dilation in different vascular beds such as mesentery, hindquarters, and kidneys [ 14 , 15 , 16 ], or by indirectly modulating the vegetative nervous system at the vascular and cardiac levels [ 17 , 18 , 19 , 20 ]. In this sense, 5-HT causes rat vascular sympatho-inhibition mainly by activation of 5-HT 1D receptors [ 18 , 19 , 21 ]. However, experimental diabetes, as well as pharmacological 5-HT modulation by the antagonism of 5-HT 2 receptor, modify the serotonergic effect on the sympathetic discharge of rat vasculature [ 22 , 23 , 24 , 25 ], maintaining the main vascular sympatholytic effect of 5-HT.…”

Section: Introductionmentioning

confidence: 99%

Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT1D Receptor Activation via NO Pathway

Fernández-González

Ordóñez

et al. 2023

IJMS

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Renal vasculature, which is highly innervated by sympathetic fibers, contributes to cardiovascular homeostasis. This renal sympathetic outflow is inhibited by 5-HT in normoglycaemic rats. Considering that diabetes induces cardiovascular complications, we aimed to determine whether diabetic state modifies noradrenergic input at renal level and its serotonergic modulation in rats. Alloxan diabetic rats were anaesthetized (pentobarbital; 60 mg/kg i.p.) and prepared for in situ autoperfusion of the left kidney to continuously measure systemic blood pressure (SBP), heart rate (HR), and renal perfusion pressure (RPP). Electrical stimulation of renal sympathetic outflow induces frequency-dependent increases (Δ) in RPP (23.9 ± 2.1, 59.5 ± 1.9, and 80.5 ± 3.5 mm Hg at 2, 4, and 6 Hz, respectively), which were higher than in normoglycaemic rats, without modifying HR or SBP. Intraarterial bolus of 5-HT and 5-CT (5-HT1/5/7 agonist) reduced electrically induced ΔRPP. Only L-694,247 (5-HT1D agonist) reproduced 5-CT inhibition on sympathetic-induced vasoconstrictions, whereas it did not modify exogenous noradrenaline-induced ΔRPP. 5-CT inhibition was exclusively abolished by i.v. bolus of LY310762 (5-HT1D antagonist). An inhibitor of guanylyl cyclase, ODQ (i.v.), completely reversed the L-694,247 inhibitory effect. In conclusion, diabetes induces an enhancement in sympathetic-induced vasopressor responses at the renal level. Prejunctional 5-HT1D receptors, via the nitric oxide pathway, inhibit noradrenergic-induced vasoconstrictions in diabetic rats.

“…Within this context, 5-HT stands out as a neurohormone capable of regulating the sympathetic nervous system; certainly, the serotonergic system has been shown to modulate peripheral sympathetic neurotransmission at both the vascular and cardiac levels 13 – 19 . With respect to perivascular sympathetic innervation in pithed rats, our research team has already demonstrated that 5-HT induces sympatho-inhibition in the vasopressor discharge, mainly through activation of prejunctional 5-HT 1A and 5-HT 1D receptors 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

Role of peripheral 5-HT5A receptors in 5-HT-induced cardiac sympatho-inhibition in type 1 diabetic rats

Hernández-Abreu

Morán

et al. 2020

Sci Rep

Self Cite

5-HT inhibits cardiac sympathetic neurotransmission in normoglycaemic rats, via 5-HT1B, 5-HT1D and 5-HT5A receptor activation. Since type 1 diabetes impairs the cardiac sympathetic innervation leading to cardiopathies, this study aimed to investigate whether the serotonergic influence on cardiac noradrenergic control is altered in type 1 diabetic rats. Diabetes was induced in male Wistar rats by streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by electrical preganglionic stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or i.v. noradrenaline bolus injections. Immunohistochemistry was performed to study 5-HT1B, 5-HT1D and 5-HT5A receptor expression in the stellate ganglion from normoglycaemic and diabetic rats. In the diabetic group, i) i.v. continuous infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT1/5A agonist 5-carboxamidotryptamine (without modifying noradrenaline-induced tachycardia), but not by the agonists indorenate (5-HT1A), CP 93,129 (5-HT1B), PNU 142633 (5-HT1D), or LY344864 (5-HT1F); ii) SB 699551 (5-HT5A antagonist; i.v.) completely reversed 5-CT-induced cardiac sympatho-inhibition; and iii) 5-HT5A receptors were more expressed in the stellate ganglion compared to normoglycaemic rats. These results show the prominent role of the peripheral 5-HT5A receptors prejunctionally inhibiting the cardiac sympathetic drive in type 1 diabetic rats.